(1) Field of the Invention
The present invention generally relates to treatments for preventing or minimizing ischemia-reperfusion injury. More specifically, the invention is directed to the administration of administration of adrenomedullin binding protein-1 to mammals at risk for ischemia-reperfusion injury.
(2) Description of the Related Art
Tissue ischemia leads to several chemical events occur that can result in cellular dysfunction and necrosis, due to lack of oxygen in the tissues as well as induction of proinflammatory cytokines, particularly tumor necrosis factor-α (TNF-α), and the interleukins IL-1β, IL-6 and IL-10. When blood flow is restored (reperfusion), another series of events occur that produces additional injury, caused to a great extent by free radical formation, believed to be produced in part by neutrophils that are activated at the reperfusion site. In many instances, the reperfusion injury is more severe than the ischemic injury, especially if the ischemia occurs for only a short period of time.
Ischemia-reperfusion injury can occur at any time blood flow is interrupted and then restored. Examples include myocardial injury following balloon angioplasty or tPA treatment; decompression fasciotomy for severe compartment syndrome following a crush injury; restoration of blood flow following a stroke; restoration of blood flow into a transplanted organ, particularly a kidney or liver; bowel disorders such as irritable bowel syndrome or Chrohn's disease; and neuropathy due to vascular dysfunction in a diabetic.
Ischemia-reperfusion injury is often treated with pentoxifilline, a methyl xanthine derivative that inhibits neutrophil activation, and/or allopurinol, a xanthine oxidase inhibitor that reduces toxic oxygen radicals. Other treatments include antibodies to neutrophil chemoattractants. However, these treatments are often ineffective or only partially effective. There is thus a need for new treatments for ischemia-reperfusion injury.
Adrenomedullin (AM), a newly reported and potent vasodilatory peptide, is an important mediator involved in both physiological and pathological states. Human AM, a 52-amino acid peptide, was first isolated and reported in 1993. AM has a carboxy terminal amidated residue and a 6-member ring structure formed by an intramolecular disulfide bond near the amino terminus, and is available commercially. Rat adrenomedullin has 50 amino acids with 2 amino acid deletions and 6 substitutions as compared to human adrenomedullin. Adrenomedullin transcripts and protein are expressed in a large number of tissues, and circulating levels of adrenomedullin were observed under normal as well as pathophysiological conditions.
In 1999, Elsasser et al. (Endocrinol. 140:4908-11) reported that specific adrenomedullin binding proteins (AMBP) exist in the plasma of several species including humans. More recently, the binding protein AMBP-1 has been identified in human plasma and has been shown to be identical to human complement factor H. AMBP-1 enhances adrenomedullin-mediated induction of cAMP in fibroblasts, augments the adrenomedullin-mediated growth of a cancer cell line, and suppresses the bactericidal capability of adrenomedullin on E. coli. 
Other studies have also shown that AM and AMBP-1 have anti-inflammatory properties in a sepsis model. That work found that adrenomedullin binding protein-1 (AMBP-1) is limiting relative to adrenomedullin during shock, which limits the effectiveness of adrenomedullin therapy for reducing deleterious effects of shock. Administration of AMBP-1 alleviates this adrenomedullin hyporesponsiveness and is thus a useful therapy for shock, either alone or with AM treatment. See U.S. patent application Ser. No. 10/729,193, filed Dec. 5, 2003.
Additionally, AM has been found to be effective in treating ischemia-reperfusion injury caused by myocardial infarction (Kato et al., Am. J. Physiol. Heart Circ. Physiol. 285:H1506-14, 2003), as well as ischemic renal injury (Nishimatsu et al., Circulation Res. 90:625-7, 2002). There is thus a need to determine whether AM treatment is effective for reducing or preventing other ischemic/reperfusion injury, and whether AM and AMBP-1 treatments are effective with ischemia/reperfusion injury. The present invention addresses that need.